James P. Zacny

College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement

This position paper from the College on Problems of Drug Dependence addresses the issues related to non-medical use and abuse of prescription opioids. A central theme throughout is the need to strike a balance between risk management strategies to prevent and deter prescription opioid abuse and the need for physicians and patients to have appropriate access to opioid pharmaceuticals for the treatment of pain. The epidemiology of prescription opioid use and abuse is reviewed. Non-medical use and abuse of prescription opioids are on the rise in the United States, illicit use of several widely prescribed opioids has increased disproportionately more than illicit use, and the prevalence of prescription opioid abuse appears to be similar to that of heroin and cocaine abuse. There is a paucity of abuse liability testing of prescription opioids, and methods should be developed to fill critical gaps in our knowledge in this area. The role of regulatory agencies in preventing diversion of prescription opioids and identifying potential sources of diversion are discussed. More research is needed to identify those populations most at risk for abusing prescription opioids, and then to develop appropriately targeted prevention programs. Treatment options are discussed; these depend on whether or not an abuser is in pain. Prescription opioid abuse has harmful ramifications for the legitimate and appropriate use of opioids, including stigmatization, opiophobia, and undertreatment of pain. Recommended steps to take include further epidemiological research, laboratory testing of prescription opioids to determine abuse liability, and clinical trials to determine the efficacy of different approaches to the prevention and treatment of prescription opioid abuse.

A review of the effects of opioids on psychomotor and cognitive functioning in humans.

The literature on the effects of opioids on psychomotor and cognitive functioning in humans is evaluated. Some studies have examined the acute and chronic effects of various opioids on different subject populations. In addition, epidemiologic studies have examined the neuropsychological functioning

Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies

&NA; Although a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the available literature on sex differences in &mgr; and mixed &mgr;/&kgr; opioid effect on acute and experimental pain. Fifty unique studies (including three unpublished studies) were included in the analyses. Across the 25 clinical studies on &mgr;‐opioids there was no significant sex‐analgesia association. Restricting the analysis to patient‐controlled analgesia (PCA) studies (irrespective of the opioid) yielded greater analgesia in women (n = 15, effect size 0.22, 95% c.i. 0.02–0.42, P = 0.028). Further restricting the analysis to PCA morphine studies yielded an even greater effect in women (n = 11, effect size = 0.36, 95% c.i. 0.17–0.56, P = 0.003). Meta‐regression indicated that the longer the duration of PCA, the difference in effect between the sexes further increased. Across experimental pain studies on &mgr;‐opioids women had greater antinociception from opioids (n = 11, effect size = 0.35; 95% c.i. 0.01–0.69, P = 0.047), which was predominantly due to 6 morphine studies. Female patients had greater &mgr;/&kgr; opioid analgesia (n = 7, effect size 0.84; 95% c.i. 0.25–1.43, P = 0.005), but no sex‐analgesia association was present in experimental studies (n = 7). Sex differences exist in morphine‐induced analgesia in both experimental pain studies and clinical PCA studies, with greater morphine efficacy in women. The data on non‐morphine &mgr; and mixed &mgr;/&kgr;‐opioids are less convincing and require further study.

Reinforcing and subjective effects of oral Δ9-THC and smoked marijuana in humans

The reinforcing and subjective effects of oral delta-9-tetrahydrocannabinol (THC) and smoked marijuana were studied in two groups of regular marijuana users. One group (N=10) was tested with smoked marijuana and the other (N=11) with oral THC. Reinforcing effects were measured with a discrete-trial choice procedure which allowed subjects to choose between the self-administration of active drug or placebo on two independent occasions. Subjective effects and heart rate were measured before and after drug administration. Smoked active marijuana was chosen over placebo on both choice occasions by all subjects. Similarly, oral THC was chosen over placebo on both occasions by all but one subject. Both active drug treatments produced qualitatively and quantitatively similar subjective effects, and both significantly increased heart rate, although the time course of effects differed substantially between the two treatments. The results demonstrate that both smoked marijuana and oral THC can serve as positive reinforcers in human subjects under laboratory conditions. The experimental paradigm used here should prove useful for identifying factors that influence the self-administration of marijuana and other cannabinoids by humans.

Subjective, psychomotor, cognitive, and analgesic effects of subanesthetic concentrations of Sevoflurane and nitrous oxide

Background: Sevoflurane is a volatile general anesthetic that differs in chemical nature from the gaseous anesthetic nitrous oxide. In a controlled laboratory setting, the authors characterized the subjective, psychomotor, and analgesic effects of sevoflurane and nitrous oxide at two equal minimum alveolar subanesthetic concentrations. Methods: A crossover design was used to test the effects of two end‐tidal concentrations of sevoflurane (0.3% and 0.6%), two end‐tidal concentrations of nitrous oxide (15% and 30%) that were equal in minimum alveolar concentration to that of sevoflurane, and placebo (100% oxygen) in 12 healthy volunteers. The volunteers inhaled one of these concentrations of sevoflurane, nitrous oxide, or placebo for 35 min. Dependent measures included subjective, psychomotor, and physiologic effects, and pain ratings measured during a cold‐water test. Results: Sevoflurane produced a greater degree of amnesia, psychomotor impairment, and drowsiness than did equal minimum alveolar concentrations of nitrous oxide. Recovery from sevoflurane and nitrous oxide effects was rapid. Nitrous oxide but not sevoflurane had analgesic effects. Conclusions: Sevoflurane and nitrous oxide produced different profiles of subjective, behavioral, and cognitive effects, with sevoflurane, in general, producing an overall greater magnitude of effect. The differences in effects between sevoflurane and nitrous oxide are consistent with the differences in their chemical nature and putative mechanisms of action.

Propofol at a subanesthetic dose may have abuse potential in healthy volunteers.

We conducted a study in which the rewarding effects of propofol were assessed in humans, using a discrete-trials choice procedure. Normal healthy volunteers (n = 12) were exposed in a blind fashion to acute bolus injections of 0.6 mg/kg of propofol twice and to a similar volume of Intralipid® twice. Then, for the next three sessions, subjects chose which drug (identified by a color code) they wished to receive. We defined propofol choosers if individuals chose propofol two or three times, and nonchoosers if they chose propofol once or not at all. By using a χ2 goodness-of-fit test of a random choice model, the choice distribution differed significantly from a random choice distribution (P < 0.005). Six subjects were choosers: four subjects chose propofol on all three choice occasions and two subjects chose the drug on 2/3 occasions (referred to hereafter as propofol choosers). Six subjects were nonchoosers: five subjects chose Intralipid® on all three choice occasions, and one subject chose Intralipid® twice (referred to hereafter as propofol nonchoosers). During sampling sessions, propofol choosers reported pleasant acute effects and no unpleasant residual effects, whereas propofol non-choosers reported either unpleasant acute subjective effects and/or residual effects from propofol. We conclude that 1) propofol may be rewarding (reinforcing) in some individuals without a history of drug abuse, and 2) further abuse liability testing is needed with this drug.

Subjective and Psychomotor Effects of Sub anesthetic Doses of Propofol in Healthy Volunteers

Propofol is increasingly being used in medical and surgical procedures in which conscious sedation of the patient is desired. The mood-altering and psychomotor effects of subanesthetic concentrations of propofol have not been well characterized. Therefore, we examined the effects of intravenous infusions of different subanesthetic doses of propofol on mood and psychomotor/cognitive performance in healthy volunteers (n = 10). A prospective, randomized, placebo-controlled, double-blind, crossover design was used in which subjects first were administered an intravenous loading dose of propofol or placebo (Intralipid) and then were infused over a 20-min period with a given dose of propofol or placebo. Each subject received placebo (Intralipid loading dose and infusion), low-dose propofol (0.08 mg/kg loading dose and 0.5 mg.kg-1.h-1 infusion), moderate-dose propofol (0.16 mg/kg loading dose and 1.0 mg.kg-1.h-1 infusion), and high-dose propofol (0.32 mg/kg loading dose and 2.0 mg.kg-1.h-1 infusion) in four sessions spaced approximately 1 week apart. Propofol induced changes in mood in a dose-related fashion. Some of these mood-altering effects lingered for as long as 30 min after termination of the infusion, but, in general mood had returned to baseline levels 1 h after termination of the infusion. Intralipid induced no changes in mood during the infusion period. Psychomotor functioning was impaired during, and anterograde amnesia was present after, the high-dose propofol infusion. These results suggest that propofol as a sedative has a spectrum of effects that are well-suited for ambulatory surgery (e.g., sedation, amnesia, and rapid and complete recovery).

Subjective, psychomotor, and analgesic effects of oral codeine and morphine in healthy volunteers

Abstract The subjective, psychomotor, and physiological effects of analgesic doses of oral codeine and morphine were examined in 12 healthy volunteers. Subjects ingested placebo, morphine 20 or 40 mg, or codeine 60 or 120 mg in a randomized, double-blind, crossover design. The smaller and larger doses of each drug were putatively equianalgesic, and the cold-pressor test was included to test this assumption. Codeine and morphine increased ratings of “feel drug effect” but had little effect on other subjective measures, including the Addiction Research Center Inventory, visual analog scales, and adjective checklists. The few subjective effects that were observed were modest and were dose-related for morphine but not for codeine. The drugs did not affect performance on Maddox-Wing, digit-symbol substitution, coordination, auditory reaction, reasoning, and memory tests. Dose-related decreases in pupil size (miosis) were observed following codeine and morphine. Ratings of pain intensity decreased in a dose-related manner for morphine but not for codeine. Plasma codeine and morphine levels varied as an orderly function of dose. These results suggest that oral codeine and morphine are appropriate drugs for outpatient pain relief because they are effective analgesics at doses that have only modest effects on mood, produce few side effects, and do not impair performance. The results also suggest a possible ceiling effect of codeine on analgesia and subjective effects.

Subjective and behavioral responses to intravenous fentanyl in healthy volunteers

Fentanyl is a mu opiate agonist which is occasionally abused by medical personnel who have ready access to the drug. We examined in healthy volunteers (N=13) the subjective and psychomotor-impairing effects of intravenous fentanyl (0–100 µg/70 kg). A randomized, placebo-controlled, crossover design was used in which subjects were injected with 0, 25 (N=6), 50 and 100 µg/70 kg fentanyl in a double-blind fashion. Subjects completed several questionnaires commonly used in abuse liability testing studies before drug injection and at periodic intervals for up to 3 h after drug injection. Subjects also completed several psychomotor tests at these times. Some aspects of psychomotor functioning (e.g., eye-hand coordination) were impaired by fentanyl. Fentanyl produced dose-related increases in ratings of “high” and “sedated,” but also tended to produce dysphoria and somatic symptomatology. Most subjects reported liking the effects of the two higher doses of fentanyl for at least a brief time after injection, but they varied widely in their liking ratings across the 3-h post-drug injection period. Despite the transient increases in liking ratings, fentanyl did not increase scores on a widely-used measure of drug-induced euphoria (morphine-benzedrine group scale of the Addiction Research Center Inventory). The present results suggest that some medical personnel who experiment with fentanyl may like it, and thus be at increased risk for abusing the drug in the future.

Systematic review: the efficacy of intermittent and on-demand therapy with histamine H2-receptor antagonists or proton pump inhibitors for gastro-oesophageal reflux disease patients.

Aim : To perform a systematic review on the efficacy of intermittent and on‐demand therapy with either histamine H2‐receptor antagonists or proton pump inhibitors for patients with erosive oesophagitis or symptomatic heartburn.